Herpes simplex virus infections are ubiquitous in all populations. HSV-2 has emerged as the major cause of genital ulcer disease worldwide and a significant risk factor for HIV acquisition. Recent studies using type-specific serologies and mucosal sampling of genital secretions for HSV have shown a remarkable variation in the clinical course of HSV-2 infections. Among persons sampled daily for HSV DNA for >30 days, the HSV detection rates vary from 0 to 100% (median 19%). Transmission studies suggest that the host, rather than the virus, is the main determinant of the severity of genital HSV-2 infection. This proposal will examine the association between HLA types and HSV-2 severity. The specific aims are: 1) To identify major histocompatibility complex (MHC) class I and II alleles associated with severe vs. mild SV-2 infection. The severity of HSV-2 is defined by follow up of >400 persons who have had virologic and clinical assessment of their infection measured by swabs of genital mucosa >30 consecutive days for HSV detection. 2) To determine if HLA class I-restricted cellular immune responses exert selective pressure on HSV-2 amino acid sequences; 3) To create a DNA repository of samples from HSV-2 infected persons with well-characterized clinical and virologic severity of disease. We hypothesize that: 1) specific HLA alleles are associated with the severity of genital HSV-2 infection; 2) the degree of homozygosity at five primary HLA loci will be associated with increasing severity of genital HSV-2 infection; and 3) HLA class I-restricted immune responses exert selective pressure on HSV-2 amino acid sequences. To examine these hypotheses, HLA genotypes at A, B, Cw, DQB1, and DRB1 loci will be determined and correlated with disease severity. The relationship between host HLA type and the predicted amino acid sequence of known HLA class I-restricted epitopes in HSV-2 isolates will be examined. These studies will result in a host DNA specimen bank of uniquely characterized cohort for further studies of innate immunity and other host factors on HSV-2 pathogenesis. As control strategies for HSV-2 are currently lacking, and candidate vaccines have had limited clinical activity, this project will provide insight into host-pathogen interaction needed for a more successful approach to vaccine development.